H. F. Roth et al.
was cooled to rt and chipped ice (1 g) was added to the 3.3 mmol). The resulting yellow solution was stirred at ꢁ781C for
vigorously stirred mixture followed by water (1 mL). The reaction 30 min, then warmed up to 01C and stirred for 1 h. The red
mixture was warmed up to rt and stirred further for 30 min solution was cooled to ꢁ781C again and a solution of Me3SnCl
before transferred to a 125 mL separatory funnel and parti- (3.3 mmol) in THF was added dropwise with vigorous stirring.
tioned. The aqueous phase was extracted with ethyl acetate The mixture was kept at the same temperature for 30 min and
(3 ꢀ 20 mL) and the organic layers were combined and washed allowed to slowly warm up to rt. A saturated aqueous NH4Cl
successively with saturated NH4Cl (3 ꢀ 10 mL) and brine solution (5.0 mL) was added and the mixture was partitioned in
(3 ꢀ 10 mL). The organic extracts were dried over Na2SO4, a 125 mL separatory funnel. Ethyl acetate (3 ꢀ 20 mL) was added
filtered and concentrated to provide a brown solid as the crude for extraction and the organic layers were combined and
product (2.84 g), which was further purified by flash column washed successively with water (3 ꢀ 10 mL) and brine
chromatography to provide compound 4 as a brown powder (3 ꢀ 10 mL). After filtration and rotatory evaporation, the organic
1
(1.45 g, 92%). H NMR (300 MHz, CDCl3) d 2.38 (d, J = 2.3 Hz, 2H), phase was concentrated to give a yellow residue, which upon
3.51 (s, 3H), 5.84 (d, J = 12.1 Hz, 1H), 6.32 (d, J = 12.2 Hz, 1H), 7.21 further flash column chromatography, delivered the desired
1
(d, J = 2.1Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.88 (s, 1H). 13C NMR compound 7 as a yellow syrup (1.11 g, 66%). H NMR (300 MHz,
(75 MHz, CDCl3) d 202.04, 138.20, 131.60, 128.65, 128.54, 125.63, CDCl3) d 0.90 (s, 9H), 2.02 (s, 9H), 3.55 (m, 2H), 3.49 (s, 3H), 7.27
124.39, 120.18, 113.15, 42.84, 27.13.
(d, J = 2.0 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.62 (s, 1H).
3-[1, 2-14C]Methoxycarbonylmethyl-5-nitro-2-phenyl-indole-
1-carboxylic acid tert-butyl ester 8
4-[(2-Bromo-4-nitro-phenyl)-tert-butoxycarbonyl-amino]-
but-2-[1, 2-14C]enoic acid methyl ester 5
A Schlenk flask was charged with compound 7 (1.11 g,
2.17 mmol), bromobenzene (0.34 mL, 3.25 mmol), Pd(PPh3)2Cl2
(40 mg, 0.05 mmol), Tri-tert-butylphosphine (20 mL, 0.11 mmol),
CuI (21 mg, 0.11 mmol), CsF (660 mg, 4.34 mmol) and anhydrous
toluene (20 mL). The suspension was heated to 1201C and
vigorously stirred for 16 h. TLC monitoring proved that all the
starting material 7 had been consumed. The brown mixture was
filtered through a short silica gel column and the column was
washed with EtOAc (3 ꢀ 5 mL). The light-colored filtrates were
combined and rotatory evaporated to dryness. The crude
product was further purified by flash column chromatography
To a solution of 4 (1.40 g, 4.4 mmol) in THF (20 mL) and saturated
aqueous NaHCO3 (5 mL) at 01C was added Boc2O (1.25 g, 5.7 mmol).
The solution was allowed to stir at rt overnight. The next morning,
the solution was transferred to a 125 mL separatory funnel and
partitioned. The mixture was extracted with ethyl acetate
(3 ꢀ 20 mL) and all the organic layers were combined and washed
successively with water (3 ꢀ 10 mL) and brine (3 ꢀ 10 mL). The
organic extracts were dried over Na2SO4, filtered and concentrated
to give a colorless residue, which after flash column chromato-
graphy purification, afforded compound 5 as an off-white solid
1
(1.79 g, 98%). H NMR (300MHz, CDCl3) d 0.88 (s, 9H), 2.41 (d, J=
1
to give compound 8 as an off-white powder (846 mg, 95%). H
2.0 Hz, 2H), 3.50 (s, 3H), 5.82 (d, J= 12.0 Hz, 1H), 6.33 (d, J=11.9Hz,
1H), 7.18 (d, J= 1.9 Hz, 1H), 7.33 (d, J= 1.9 Hz, 1H), 7.85 (s, 1H). 13C
NMR (75 MHz, CDCl3) d 201.18, 195.66, 136.78, 131.52, 127.48,
127.04, 126.60, 123.30, 117.10, 114.16, 45.84, 36.76, 25.28, 15.28.
NMR (300 MHz, CDCl3) d 0.87 (s, 9H), 3.36 (m, 2H), 3.46 (s, 3H),
7.27–7.33 (m, 6H, Ar-H), 7.39 (d, J = 2.1 Hz, 1H), 7.68 (s, 1H). 13C
NMR (75 MHz, CDCl3) d 205.15, 202.31, 133.20, 130.17, 129.60,
128.63, 128.28, 126.14, 125.85, 125.37, 125.02, 124.75, 123.86,
123.06, 122.58, 122.38, 35.35, 28.78, 27.26, 18.40.
3-[1, 2-14C]Methoxycarbonylmethyl-6-nitro-4H-quinoline-1-
carboxylic acid tert-butyl ester 6
8-Nitro-6H,11H-benzo[a][4, 5-14C]carbazol-5-one 9
A round bottom flask was charged with compound 5 (1.74 g,
4.2 mmol), Pd(OAc)2 (112 mg), Ph3P (131 mg, 0.5 mmol), NaHCO3
(706 mg, 8.4 mmol), LiCl (178 mg, 4.2 mmol) and anhydrous DMF
(20 mL). The flask was heated to 1301C and the reaction was
monitored at every 1 h interval. After all the starting material had
been consumed, the flask was cooled to rt and the mixture was
filtered through a small silica gel pad to remove all the precipitates.
The silica gel pad was washed with EtOAc (3 ꢀ 10 mL) and the
filtrates were combined and washed successively with water
(3 ꢀ 10 mL) and brine (3 ꢀ 10 mL). The organic layers were dried
over Na2SO4, filtered and concentrated to give a yellow residue
(1.61 g) as the crude product. After a flash column chromatography,
the desired compound was obtained as an off-white powder
(1.11 g, 76%). 1H NMR (300 MHz, CDCl3) d 0.89 (s, 9H), 3.41 (m, 2H),
3.46 (s, 3H), 6.18 (s, 1H), 7.28 (d, J= 1.9 Hz, 1H), 7.32 (d, J=2.1Hz,
1H), 7.52 (s, 1H). 13C NMR (75MHz, CDCl3) d 204.36, 197.28, 129.20,
129.15, 128.41, 128.00, 125.70, 123.30, 123.10, 119.16, 35.25, 33.26,
26.73, 17.26. HRMS: Cacd for C17H20N2O6 348.1321, Found 348.1328.
To a solution of LiOH (51 mg, 2.14 mmol) in H2O (1.0 mL) at 251C
was added a solution of 8 (800 mg, 1.95 mmol) in anhydrous THF
(5 mL). To this solution was added H2O2 (30%, 5.0 mL). The
solution was stirred at 251C until the TLC monitoring showed
that all the starting material 8 had been consumed. After
cooling to 01C, the solution was acidified with aqueous HCl
(1.0 N) to pH 1–2. The mixture was extracted with EtOAc
(3 ꢀ 10 mL) and all the extracts were combined and washed
successively with water (3 ꢀ 10 mL), brine (3 ꢀ 10 mL) and dried
over Na2SO4. The organic solvents were removed under reduced
pressure to give a white powder (741 mg), which was dissolved
in anhydrous pyridine (1.5 mL) and treated with cyanuric
chloride (370 mg, 2.0 mmol) at 01C. The mixture was allowed
to warm up to rt and stirred for 3 h. After diluted with EtOAc
(20 mL) and washed with water (3 ꢀ 5 mL) and brine (3 ꢀ 5 mL),
all the solvents were removed under reduced pressure to deliver
a colorless syrup (822 mg), which was used for next step reaction
without further purification. The syrup was dissolved in
anhydrous CH2Cl2 (10 mL) and cooled to ꢁ781C. With vigorous
stirring, AlCl3 (267 mg, 2.0 mmol) was added in one portion.
The solution was allowed to stir at this temperature for 1 h and
3-[1, 2-14C]Methoxycarbonylmethyl-6-nitro-2-trimethylstan-
nanyl-4H-quinoline-1-carboxylic acid tert-butyl ester 7
To a ꢁ781C solution of 6 (1.15 g, 3.3 mmol) in anhydrous THF slowly warmed up to rt and stirred for another 1 h. The mixture
(15 mL) was added freshly prepared LDA (1.2 M in THF, 2.8 mL, was again cooled to 01C and aqueous HCl (4.0 N, 2.0 mL) was
Copyright r 2011 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 272–277